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Spitzer, B.

Publications and source records attributed to Spitzer, B..

2 recordsLinked to original sources

Neural structure mapping in human probabilistic reward learning

Humans can learn abstract concepts that describe invariances over relational patterns in data. One such concept, known as magnitude, allows stimuli to be compactly represented by a single dimension (i.e. on a mental line), for example according to their cardinality, size or value. Here, we measured representations of magnitude in humans by recording neural signals whilst they viewed symbolic numbers. During a subsequent reward-guided learning task, the neural patterns elicited by novel complex visual images reflected their pay-out probability in a way that suggested they were encoded onto the same mental number line. Our findings suggest that in humans, learning about values is accompanied by structural alignment of value representations with neural codes for the concept of magnitude.

neuroscience

MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia

HIGHLIGHTSO_LIMEF2C S222 phosphorylation is a specific marker of chemotherapy resistance in diagnostic AML patient specimens.\nC_LIO_LIMEF2C S222 phosphorylation is dispensable for normal hematopoiesis in mice, as established using genome editing in vivo, but is required for MLL-AF9 induced leukemogenesis.\nC_LIO_LIMARK kinases specifically phosphorylate MEF2C S222, potentiating its transcriptional activity.\nC_LIO_LIChemical inhibition of MARK-induced MEF2C phosphorylation overcomes chemotherapy resistance of and exhibits selectivity toxicity against MEF2C-activated human AML cells.\nC_LI\n\nSUMMARYIn acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, and induced by MARK kinases in cells. Treatment with the selective MARK inhibitor MRT199665 caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.

cancer biology